It is known that oxygen-derived radical species are important mediators of several forms of tissue damage, such as ischemic and traumatic injuries to organs and tissues, inflammatory responses and injuries which result from the intra-cellular metabolism of chemicals and drugs. In particular, oxygen-derived radical species have been suggested as destructive forces in such maladies as head and spinal cord injury, stroke, shock, Parkinsonism, muscular dystrophy, emphysema, ARDS (acute respiratory distress syndrome), asthma, aging, post-myocardial infarct tissue destruction, drug toxicity, radiation damage, transplant rejection and burn damage.
In addition to their adverse effects on various other body tissues, oxidation reactions can also cause damage to the eye. It is known, for example, that the aqueous humor of the eye is rich in hydrogen peroxide and that the anterior tissues bathed by the aqueous humor exist in an extraordinarily oxidalive environment. It is further known that prolonged exposure of the eye to light of certain wavelengths can cause harm to anterior, posterior and other tissues of the eye. Indeed, prolonged exposure to light produces oxidative damage in many tissues such as the lens, retina and retinal pigmented epithelium. Additionally, chronic exposure to light and to an oxidative environment is believed to induce cumulative damage, which, depending on the severity of the exposure and the susceptibilities of the individual exposed can result, in the best of cases, in normal aging and discomfort and, in the worst of cases, in pathological disorders and loss of vision.
In addition to light exposure, such a cascade leading to the production of harmful oxidative species is initiated by inflammation, by trauma, by ischemia, by hemorrhaging by stimulation by a variety of drugs and endogenous cell regulators, by pressure exertion on tissues as occurs diurnally as a result of intraocular pressure changes in the anterior chamber of the eye, and indeed by a host of processes both normal and abnormal that occur continuously in the eye. Polyunsaturated fatty acids are also readily subjected to chemical (non-enzymatic) oxidation to yield hydroperoxides, hydroxy fatty acids and malondialdehyde, materials which can contribute to the overall damage that accumulates with time.
Thus, oxidative processes are now known to a play a role in age-related cataracts, light-induced retinal damage, other retinopathies such as diabetic retinopathy and age-related macular degeneration, inflammatory damage (such as that seen in uveitis), vascular leakage and edema (as in cystoid macular edema), accidental or surgical trauma, angiogenesis, corneal opacities, retrolental fibroplasia and some aspects of glaucoma.
To counteract the harmful effects of the oxidative processes described above, the body naturally produces a number of defensive compounds such as .alpha.-tocopherol (vitamin E, which is an antioxidant), ascorbic acid, glutathione, catalase and superoxide dismutase. Thus, vitamin E, is known to be a scavenger of both lipid peroxyl radicals and oxygen radicals, as well as to have a membrane-stabilizing action. Indeed, it is believed that chronic dietary vitamin E supplementation can attenuate postischemic cerebral (hypoperfusion) by inhibiting the lipid peroxidative process.
In order to enhance the eye's ability to protect from damaging oxidative processes such as can occur with aging or due to a sudden trauma, it has been proposed to supply vitamin E to the eye by oral administration in view of its known ability to inhibit oxidative processes. Vitamin E does scavenge free radicals and function as an antioxidant. However, it must be given chronically to have any effect. Moreover, even when administered chronically with other antioxidants, such as glutathione and vitamin C, the results are at best mixed.
A group of 21-aminosteroids has been found to act as antioxidants, and some aminosteroids have been employed intravenously, intraperitoneally and orally in the treatment of central nervous system injury, head and spinal injury, and edema associated with acute stroke. It has been reported that intravenous administration of a citrate buffered saline solution of 0.15% by weight of U-74600F for treatment of spinal cord or brain injury has been effective to arrest lipid peroxidation therein. , It is also known that in performing toxicology studies with various drugs, polysorbate 80 and hydroxypropylcellulose and the like can be used as suspending agents in low viscosity formulations.
International Publication No. WO 87/01706, published Mar. 26, 1987, which discloses a number of aminosteroids and their therapeutic use in a variety of contexts, as well as administration techniques and dosages, does not disclose treatment or prevention of ophthalmic diseases or disorders. Nor does it disclose topical application to the eye or administration by intraocular injection. Moreover, prior art formulations which cannot be comfortably and effectively applied to the eye have limited applicability.
Applicants' great grandparent application Ser. No. 07/537,062, now U.S. Pat. No. 5,124,154, discloses methods and compositions which are designed to enhance the ability of the tissues of the eye to respond to trauma, to aging, to surgery, to the threat of glaucoma by increasing intraocular pressure, to the potential loss of vision from progression of macular degeneration and the like by supplementing, both acutely and chronically, the natural ability of the eye to resist oxidative damage. In one aspect, the '154 invention discloses methods of arresting processes (particularly oxidation processes) causing damage to the eye of a human or other animal that is subject to intraocular damage (particularly oxidative intraocular damage) and in need of improved visual function or prevention of its loss from such damage, wherein certain amino-substituted steroids which function as a therapeutic agent (particularly an antioxidant agent) are administered in an inert vehicle to the eye tissue by intraocular injection or topically. In another aspect, the '154 invention discloses methods of preventing or treating ophthalmic diseases or disorders in a human or other animal that is subject to intraocular damage (particularly oxidative intraocular damage) and in need of improved visual function or prevention of its loss from such damage, wherein an ophthalmically effective amount of certain amino-substituted steroids which function as a therapeutic agent (particularly an antioxidant agent) is administered, in an inert vehicle, to arrest presses (particularly oxidation processes) damaging to the eye. Compositions useful in the disclosed methods are also described.
The aminosteroids disclosed in International Publication No. WO 87/01706 and great grandparent U.S. Ser. No. 07/537,062 (now U.S. Pat. No. 5,124,154), as well as in parent Ser. No. 07/933,574, thus are valuable therapeutic agents, particularly as a consequence of their antioxidant activity. However, the aminosteroids suffer from stability problems and they can cause irritation. Moreover, because they are potent antioxidants, the aminosteroids are especially sensitive to oxidative degradation; moreover, these compounds are subject to hydrolytic degradation and rearrangement. Such instability can severely limit the usefulness of pharmaceutical compositions containing the aminosteroids, for example, by drastically shortening the shelf-life of the formulations and/or requiting stringent control of storage conditions. The aminosteroids also are known to be highly insoluble in water, even in salt form; such insolubility can seriously hamper efforts to utilize the compounds to their full potential. There is thus a serious need for improved pharmaceutical compositions comprising the aminosteriods and for methods for the stabilization of such pharmaceutical compositions.
Sustained release ophthalmic formulations of an ophthalmic drug and a high molecular weight polymer to form a highly viscous gel have been described in Schoenwald et al U.S. Pat. No. 4,271,143, issued Jun. 2, 1981 and Schoenwald et al U.S. Pat. No. 4,407,792, issued Oct. 4, 1983.
U.K. Patent Application GB 2007091 A, published May 16, 1979, describes an ophthalmic composition in the form of a gel comprising an aqueous solution of a carboxyvinyl polymer, a water-soluble basic substance and an ophthalmic drug, the gel having a pH of 5 to 8 and a viscosity of 1,000 centipoises to 100,000 centipoises at 20.degree. C.
U.K. Patent Application GB 2013084 A, published Aug. 8, 1979, describes an aqueous gel for application to the conjunctival sac of the eye comprising an ophthalmic drug and a polymer having carboxylic or anhydride functional groups and a molecular weight in excess of 1,000,000, such as carboxypolymethylene, carboxyvinyl and ethylene maleic anhydride polymers.
Robinson U.S. Pat. No. 4,615,697, issued Oct. 7, 1986, discloses a controlled release composition and method of use based on a bioadhesive and a treating agent, such as an anti-inflammatory agent. The bioadhesive is a water-swellable, but water-insoluble, fibrous, cross-linked carboxy-functional polymer having a plurality of repeating units of which about 80 percent contain at least one carboxyl functionality and a cross-linking agent which is substantially free from polyalkenyl polyethers.
Davis et al copending application Ser. No. 07/544,518, filed Jun. 27, 1990, now U.S. Pat. No. 5,192,535 and assigned to the assignee hereof, describes formulation of lightly cross-linked polymers, preferably ones prepared by suspension or emulsion polymerizing at least about 90% by weight of a carboxyl-containing monoethylenically unsaturated monomer such as acrylic acid with from about 0.1% to about 5% by weight of a polyfunctional, and preferably difunctional, cross-linking agent such as divinyl glycol (3,4-dihydroxy-1,5-hexadiene), having a particle size of not more than 50 .mu.m in equivalent spherical diameter, with an ophthalmic medicament, e.g., the steroid fluorometholone, into suspensions in aqueous medium in which the amount of polymer ranges from about 0.1% to about 6.5% by weight, based on the total weight of the aqueous suspension, the pH is from about 3.0 to about 6.5, and the osmotic pressure (osmolality or tonicity) is from about 10 mOsM to about 400 mOsM. These new topical ophthalmic medicament delivery systems have suitably low viscosities which permit them to be easily administered to the eye in drop form, and hence to be comfortably administered in consistent, accurate dosages. These suspensions will rapidly gel in the eye after coming into contact with the eye's tear fluid to a substantially greater viscosity than that of the originally-introduced suspension and thus remain in place for prolonged periods of time to provide sustained release of the ophthalmic medicament. See International Publication Number WO 92/00044 published Jan. 9, 1992, which claims priority from U.S. Ser. No. 07/544,518, U.S. Pat. No. 5,192,535 and see also International Publication No. WO 89/06964, published Aug. 10, 1989, which claims the priority of the parent and grandparent applications upon which Ser. No. 07/544,518 U.S. Pat. No. 5,192,535 is based.
It has not been heretofore suggested, however, that lightly cross-linked carboxy-containing polymers could be used to stabilize aminosteroids in pharmaceutical formulations. It was also not known that aminosteroids disclosed in International Publication No. WO 87/01706 and great grandparent U.S. Ser. No. 07/537,062 (now U.S. Pat. No. 5,124,154) would be compatible or stable with lightly cross-linked carboxy-containing polymers.